An Open Label Prospective Study on Uricosuric Effects of Losartan in Hypertensive Patients with Hyperuricaemia

“AN

HYPERURICAEMIA”

DISSERTATION SUBMITTED TO

THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY

IN PARTIAL FULFILLMENT FOR THE AWARD OF THE DEGREE OF DOCTOR OF MEDICINE

IN

PHARMACOLOGY

DEPARTMENT OF PHARMACOLOGY TIRUNELVELI MEDICAL COLLEGE

BONAFIDE CERTIFICATE

This

is

to

certify

that

the

dissertation

entitled

“AN

submitted by DR.BANUPRIYA K to the Tamilnadu Dr. M.G.R. Medical

University, Chennai, in partial fulfillment of the requirement for the award

of the Degree of Doctor of Medicine in Pharmacology during the academic

period 2014

–

2017 is a bonafide research work carried out by her under

direct supervision & guidance.

PROFESSOR AND H.O.D.

DEAN

Department of Pharmacology,

Tirunelveli Medical College,

Tirunelveli Medical College,

Tirunelveli.

CERTIFICATE

This is to certify that the dissertation

entitled

“AN

presented herein by DR.BANUPRIYA K is an original work done by her in

the Department of Pharmacology, Tirunelveli Medical College , Tirunelveli

for the award of the Degree of Doctor of Medicine in Pharmacology during

the academic period of 2014-2017.

Place : Tirunelveli

GUIDE

Date :

Department of Pharmacology

Tirunelveli Medical College

DECLARATION

I solemnly declare that the dissertation titled

“AN OPEN LABEL

”

is done by

me in the Department of Pharmacology, Tirunelveli Medical College,

Tirunelveli.

The dissertation is submitted to The Tamilnadu Dr.M.G.R.Medical

University in partial fulfillment for the award of the degree of Doctor of

Medicine in Pharmacology.

Place: Tirunelveli

DR. BANUPRIYA K,

Date:

Postgraduate student,

M.D Pharmacology,

Department of Pharmacology,

Tirunelveli Medical College,

ACKNOWLEDGEMENT

First of all, I am grateful to the Almighty for the good health and wellbeing

that were necessary to complete this research work.

I am greatly indepted to Dr. K. Sithy Athiya Munavarah MD., Dean,

Tirunelveli Medical College and Dr. S.M. Kannan MD.,Vice Principal.

Tirunelveli Medical College , Tirunelveli for their valuable support and generous

permission for doing this research work.

I wish to thank with due respect and deep gratitude to Dr. J. Ezhil Ramya

M.D., Associate Professor and Head of the Department of Pharmacology for her

inspiration, guidance and kind help rendered in completing this dissertation.

I would like to express my deepest thanks to Dr.B.Meenakshi M.D.,Associate

Professor for giving kind advice, aspiring guidance, motivation and

encouragement throughout the research.

With deep sense of gratitude , I thank the faculties of the department of

medicine for sharing their implicit knowledge, support and encouragement during

I am immensely grateful to Dr. A. Dulcie Celia M.D.,Assistant

Professor, Dr.A.Geetha Rani M.D., Assistant Professor , & Dr.Shanthi M.D.,

Assistant Professor for their support and advice provided during the research work.

I would like to thank the post graduates of Department of Pharmacology,

for their friendly advice and sharing their illuminating views related to this study.

I also express my sincere thanks to my family members for their moral

CONTENTS

S.No. Topics

Page No.

1. INTRODUCTION

1

2. REVIEW OF LITERATURE

4

3. AIM OF THE STUDY

64

4. METHODOLOGY

65

5. RESULTS

73

6. DISCUSSION

85

7. CONCLUSION

91

8. APPENDIX

I.

Informed Consent Form

II.

EQ-5D Questionnaire

III.

Proforma

IV.

Master chart

V.

Abbreviations

1 INTRODUCTION:

Hypertension is a worldwide epidemic defined as “ Blood pressure in excess of 140/90mmHg”.Around one billion people are estimated to have hypertension, contributing to more than 7.1million deaths per year1_{.According to} the ICMR survey report, the prevalence of hypertension varied from 17-21% in all the states with marginal rural urban differences2.Genetic factor, fetal factor and environmental factors like alcohol,obesity,sodium intake, insulin resistance, stress and humoral mechanism contribute to the etiology of hypertension3_{.Hypertension} has earned the designation “silent killer” because it is asymptomatic, but it can

progressively harm the cardiovascular system4_{.Forceful flow of blood through} cardiovascular system can damage the arterial walls and heart muscle. It eventually contributes to a myocardial infarction. Hypertension can damage the cerebral and renal vessels resulting in stroke and renal disease respectively4. The goal of therapy in hypertension is to reduce the cardiovascular risk of the patients by treating co-morbid conditions and preventing hypertensive end organ damages5_.

2

acid in hypertension may be due to reduced renal blood flow and ischemia which will stimulate urate reabsorption and increase in uric acid synthesis respectively8_.

Hyperuricaemia is associated with dysfunction of endothelium, disruption of oxidative metabolism, platelet adhesion and aggregation6, 7_{.Moreover, serum} uric acid is positively correlated with blood pressure, body mass index, levels of fasting plasma glucose, triglycerides, high-sensitivity CRP and inversely associated with HDL-c7_{. Losartan is an antihypertensive drug which blocks the} angiotensin II type1 receptors. It also has pleiotropic uricosuric effect by reducing postsecretory reabsorption of uric acid in the proximal tubule of the kidney by inhibiting urate/anion exchanger with placebo like side effect profile. More over this hypouricemic effect does not occur with other angiotensin receptor blockers9,10.According to JNC-8 guidelines, blockade of renin angiotensin aldosterone system is the new first-line therapy for high risk hypertensive patients, so losartan can be given as initial therapy for newly diagnosed hypertensive patients less than 55years old11_.

3

other risk factors like obesity,dyslipidemia and hyperglycemia for the assessment of overall cardiovascular risk6_.

4 Hypertension definition and epidemiology:

Hypertension is defined as usual office blood pressure of 140/90mmHg or higher12_{.Raised arterial pressure is the most important public health issue in the} western world. Though it is commonly asymptomatic it can be easily detected and treated. But lethal complications can arise when it is untreated13_.

Increasing systolic BP and diastolic BP will increase the risk of morbidity and mortality; for example high systolic pressure is associated with 2-3 fold increase in cardiac mortality3_{.However, epidemiologic studies have confirmed} the risk for stroke and cardiovascular disease even with low BP values (for eg: 115/75 mmHg). The artificial dichotomy between “normotension and “hypertension” may delay the intervention until the manifestations of irreversible

vascular disease occurs by elevated BP that were considered normal previously. So the guideline committees continue to debate how far to lower blood pressure with antihypertensive medications and whether to initiate drug therapy for high risk patients with prehypertensive range of 120 to 139/80 to 89mmHg14_.

5

In India 6-15% of the adults in different surveys have been shown to be suffering from hypertension. At least 8% population is hypertensive in most of the countries. The prevalence of hypertension is not much different in developed and developing countries15_{.Affecting more than one million people worldwide, arterial} hypertension is the common cause of visit to a physician and the leading cause of death.

It is the easily recognized and treatable risk factor for myocardial infarction, stroke, cardiac failure, aortic dissection, atrial fibrillation and end stage renal disease. It is estimated that 1.5 billion persons (one third of the world’s population) will be affected by hypertension due to increasing rates of obesity and aging of population by the year 2025. At present 47% of ischemic heart disease and 54% of strokes occurs due to high BP12.

Risk Factors:

Aging and Pulse Pressure:

6

hypertension occurs with isolated systolic hypertension12_{. Among elderly, systolic} blood pressures of women are higher than men. Among adults, diastolic BP increases progressively with age until 55 years, after which it tends to decrease. The consequence is a widening of pulse pressure beyond the of age 60 years16

Gender and Race/Ethnicity:

Due to the protective effect of estrogen, hypertension is less common in menstruating females17.Hypertension is more prevalent among white population of several European nations, although hypertension is increasing in developed countries due to westernization.

Exacerbating factors: Obesity:

Associated with an increased intravascular volume, activated RAAS, elevated cardiac output and increased sympathetic nervous system. So weight loss can lower the BP modestly18_.

Sleep apnea:

Treatment with continuous positive airway pressure will show improvements in blood pressure.

Increased salt intake:

7 Alcohol and Cigarette smoking:

These two may rise blood pressure by elevating the plasma catecholamines.

Exercise:

Aerobic exercise will lower BP in people with sedentary life style. Others:

The relation between stress and hypertention has not been established18 Polycythemia increases blood viscosity and raises blood pressure.

NSAIDs increases blood pressure by 5mmHg and should be avoided in hypertensive patients.

Low potassium in diet can contribute to hypertension so an intake of 90mmol/d is recommended.

Associated factors: Metabolic syndrome:

Metabolic syndrome refers to hypertension with abdominal obesity, insulin resistance, elevated catecholamines, elevated inflammatory markers like C - reactive protein and dyslipidemia with high plasma triglyceride, low high-density lipoprotein. This complex of abnormalities leads to adverse cardiovascular outcomes.

8 Hyperuricaemia:

Hypertension together with hyperuricaemia is a part of the syndrome X. Hyperinsulinemia in metabolic syndrome will elevate sodium reabsorption and will reduce elimination of uric acid. Lowering of uricaemia is indicated in these patients as they remain as a risk factor for cardiovascular disease21_{.Various studies} have confirmed the association between cardiac risk and elevated uric acid among patients with hypertension.

Twenty five percent of untreated hypertensive patients, fifty percent of hypertensive patients taking diuretics and more than seventy five percent patients with malignant hypertension have high uric acid level. Also genetic and dietary factors influence uric acid levels. Baseline uric acid is significantly associated with an increased rate of outcome in the LIFE study of fatal or non fatal myocardial infraction,cardiovascular death and fatal or non fatal stroke6.Various trials implicated that hyperuricaemia may be an independent risk factor for hypertension related mortality and morbidity22_.

9

A meta-analysis confirmed that elevated uric acid is risk factor for incident hypertension and the risk is more in women and young individuals 24_.

Genetic Determinants:

Adoption, twin, and family studies document a significant heritable component to elevated BP. Family studies conducted on a background of uniform environment shows a 15–35% heritability of hypertension. In twin studies, it was 30–40% in females twins and 60% in males twins. Concordance of BP is greater for monozygotic twins than that of dizygotic twins.

Hypertension is a polygenic disease where one or more genes act along with other risk factors contributing to elevated BP25_.

Secondary causes of hypertension:  Genetic syndromes

 Coarctation of the aorta

 Primary hyperaldosteronism, Cushing syndrome,

pheochromocytoma

 Hypertension associated with pregnancy, estrogen use

 Kidney disease, renal vascular hypertension, hypercalcemia

10 JNC 7 Classification 13,26_:

Categories SBP(mm/Hg) DBP(mm/Hg)

BP in normal range <120 <80

Prehypertension 120-139 80-89

Stage one hypertension 140-159 90-99

Stage two hypertension ≥160 ≥100

Isolated systolic hypertension

>140 <90

Pathogenesis of hypertension: Blood pressure:

Arterial pressure is a product of cardiac output and peripheral vascular resistance. Cardiac output is again a product of stroke volume and heart rate.Stroke volume is linked to myocardial contractility and size of the vessels. Peripheral vascular resistance varies with anatomic and functional changes in small vessels. Elevated blood pressure may be due to elevated cardiac output and/or elevated peripheral vascular resistance13_.

Increased cardiac output:

1) Expanded fluid volume due to excessive salt consumption or may be because of kidney dysfunction causing retention of sodium

11 Increased peripheral vascular resistance:

1) Functional vascular constrictions  Sympathetic nervous system overstimulation  Excess stimulation of RAAS

 Endothelial derived factors

 Genetic alterations of cell membranes

2) Structural vascular hypertrophy

 Hyperinsulinemia due to obesity or metabolic syndrome  Sympathetic nervous system overstimulation

 Excess stimulation of RAAS  Endothelial derived factors

 Genetic alterations of cell membranes

Essential hypertension:

12

Figure 1:Pathophysiological mechanisms of hypertension27_:

Phases of Essential Hypertension: Phase 1:

13

Salt-resistant hypertension in this phase is due to intermittent ischemia caused by fluctuant levels of uric acid and intermittent activation of sympathetic system. Since the kidney is uninjured, the pressure natriuresis remains unaffected. In these individuals sodium loading will result in exaggerated natriuresis28

Phase 2:

On disease progression, arteriolosclerosis of renal vessels associated with tubulointerstitial inflammation will develop which will lead to salt sensitive, renal and volume dependent hypertension. Understanding these phases of hypertension helps us in the prevention and treatment of underlying process29_.

More recently, there is proposed theory of role for afferent arteriolar renal vasoconstriction in causing hypertension30_{.This may be explained by the}

mechanism in which renal ischemia attracting the leukocytes and oxidative stress scavenging the nitric oxide in kidney will lead to renal vasoconstriction and causing a heterogenic renin expression. This renal injury will activate the sympathetic system leading to retention of sodium and volume dependent hypertension31_.

HYPERURICAEMIA - A MECHANISM FOR ESSENTIAL HYPERTENSION:

Epidemiologic evidence:

14

hypertension, a serum uric acid of >5.5 mg/dL was observed in 89% of essential hypertensive subject, in 30% of those with secondary hypertension and in 0% of control subjects or “white coat” hypertensives24_.

Animal studies:

Wide literature review on animals supports the role of uric acid level in the pathogenesis of hypertension32. Animal studies with induced hyperuricaemia in rats activated RAAS and resulted in dysfunction of endothelium demonstrating elevated BP caused by increased urate levels33

Phase 1:

Rise in BP caused by renal vasoconstriction as a result of RAAS activation and oxidative stress was always reversible in phase I by reducing serum uric acid. The renal vasoconstriction is induced by AgII infusion in animal models that were fed on high salt diet.

Phase 2:

15 Figure 2: Uric acid and hypertension32_:

Human data:

Experimental animal and human data shows that individuals with hyperuricaemia are at greater risk for hypertension with renal complications. This mechanism is less implicated in elderly individuals, where the stiffening of the aorta is the primary reason 34_.

16 Uric acid level and incident hypertension:

The threshold for hypertension is not dependent on monosodium crystals

formation. It could be a lower value like 5.0-5.5 mg/dL which is much lower than

the supersaturation reading of 6.8 mg/dL.

A meta-analysis demonstrates a pooled risk ratio of 1.13 for new onset hypertension for every 1mg/dL raise in the uric acid level36.

17

Mechanism for vascular smooth muscle activation by uric acid:

URAT1 is a transporter that promotes the entry of uric acid in vascular

smooth muscles. Upon entry protein kinases and transcription factors are activated

which results in the release of growth factors like chemokines (monocyte

chemoattractant protein-1), platelet derived growth factor, C-reactive protein,

vasoconstrictors (cyclooxygenase II generated thromboxane) and activators of

RAAS.38

Figure 4: Activation of smooth muscles by uric acid29_:

Hyperuricaemia can result in glomerular hypertension even in the early days of essential hypertension.39

Koch’s postulates and hyperuricaemic hypertension25:

An elevated serum uric acid predicts the development of elevated blood

pressure

18

In rats, raising the uric acid with uricase inhibitor increases the blood pressure

with renal hemodynamic and pathological features as observed in human hypertension

Lowering uric acid level in animals was positively correlated with decrease in

blood pressure

Pilot studies in humans also suggest that lowering serum uric acid can reduce

primary hypertension especially in adults.

Uric acid- Chemical properties and Biological importance:

Uric acid (2, 6, 8 trioxypurine-C5H4N4O3) is an endogenous organic compound which is synthesized in the liver and eliminated through kidney mainly. It is a purine metabolism end product in humans.

 Normal value of serum uric acid3.5 to 7 mg/dl in humans

 The value is 0.5-1 mg/dL lower for women

 Renal reabsorption of uric acid and diet rich in purines contribute to

high serum uric acid 40_.

It has antioxidant property due to its double bond but in the presence of altered environment like obesity it becomes a strong oxidant41

Uricaemia and aging:

 Uric acid level increases on aging

19 Uric acid production:

Produced from xanthine utilizing the enzyme xanthine oxidase43_.

Uric acid excretion:

 10% only eliminated via kidneys

 Remaining 90% is reabsorbed

Transporters involved in urate reabsorption are 1. SLC22A12 (URAT 1) present in tubular kidney

2. SLC2A9 present in kidney and basolateral in tubule cells

By inhibiting URAT 1, drugs like probenecid, benzbromarone and losartan can lower the uric acid levels. Intestine is important for about 20% excretion of uric acid via ABCG2 transporter23

The factors influencing the renal uptake of uric acid: Serum levels of uric acid

Volume status

Factors affecting renal blood flow

Reabsorption of uric acid in kidney is competitive with organic acids (monocarboxylic) which can be blocked by lactic acid, ketone bodies and oxalic acid

Factors increasing elimination of uric acid: Volume expansion

20 Factors increasing uric acid concentration:

Acute renal failure also increases uric acid by decreased renal excretion.

Drugs like ciclosporin, ethambutol, pyrazinamide and cytotoxic chemotherapy

can raise the serum urate 44_.

Figure 5:Drugs affecting uric acid synthesis and elimination23:

Factors influencing the concentrations of uric acid: Diet

Obesity

21 Diet:

 Purine-rich food items like beer, veal, bacon, meat, mutton, turkey, pork,

duck and goose can raise uric acid

 Meat and seafood are associated with raise in uric acid.

 Large fructose intake will lead to depression of intracellular phosphate

which hinders the ATP formation resulting in hyperuricaemia.

 Vitamin-C, coffee and dietary product intake is inversely related to uric

acid.

Obesity and Metabolic syndrome :

Diabetic patients with hypertension and elevated uric acid are at risk of cardiovascular complications45. High uric acid can rise the odds ratio by 1.6 for developing metabolic syndrome in obese persons46_.

Hyperisulinemia in metabolic syndrome will reduce the uric acid excretion leading to hyperuricaemia and moreover synthesis of fatty acids in dyslipidemia will promote purine synthesis thereby elevating serum uric acid.

22 Figure 6:Determinants of Hyperuricaemia40_:

Kidney function in relation with uric acid:

Hyperuricaemia and low GFR of 60 ml/min is associated with a relative risk of 2.4 for new onset hypertension when compared to individuals with low serum uric acid. This association between uric acid and new onset hypertension is independent of traditional risk factors.

In patients with already impaired renal function, hyperuricaemia will lead to arteriosclerosis of renal vessels and glomerular hypertension. And also increased risk of insulin resistance which can result in raised blood pressure is more often seen with concomitant kidney disease with hyperuricaemia 48_.

End organ damage in hypertension due to hyperuricaemia:

23 Hyperuricaemia and incidence of CAD:

Even after adjusting the confounding factors, the incidence of cardiovascular disease in individuals with high left ventricular mass index and hyperuricaemia was found to be 2.4 times higher than their controls with normal cardiac function and urate levels49_.

For every 1mg/dl raise in serum uric acid, the risk of cardiac death increases by 12% and this risk are more common in females when compared to men 50_.

Mechanism of Target Organ Damage:

Left ventricular hypertrophy occurs as a compensatory mechanism against abnormal loading conditions and it is the leading step towards the development of full blown cardiovascular disease. Higher uric acid and left ventricular mass index leads to cardiac and renal morbidity manifested by prolonged and uncontrolled hypertension, high pulse pressure, worsening of dyslipidemia and low creatinine clearance. Even after adjusting other clinical risk factors, high serum uric acid level, left ventricular mass index and age are important predictors for cardiovascular disease.

24

monocyte chemoattractant protein-1(chemokine) in the vascular smooth muscle cells, is importantly linked to cardiovascular disease.

Decreased myocardial contraction with severe diastolic filling abnormalities and the damaged myocardium requiring more oxygen is the primary mechanism behind the association of left ventricular hypertrophy and CAD. Severe relaxation impairment of ventricles were observed in hyperuricaemic individuals with left ventricular hypertrophy and this “impaired ventricular relaxation” is linked with the risk of cardiovascular disease.

In addition, uric acid has found to be a proven excellent marker for endothelial dysfunction and ischemia of tissues leading to the development of atherosclerosis. Uric acid itself may induce left ventricular hypertrophy. In experimental in vivo and in vitro animal studies, inflammatory mediators such as cytokines, tumor necrosis factor and various protein kinases released by uric acid has shown to induce cardiac hypertrophy in animals.

Since serum uric acid has direct relationship with left ventricular mass index and severity of target organ damage, the assessments of these factors by echocardiography might be useful and sensitive in detecting those individuals with cardiovascular disease.

Nondippers in essential hypertension:

25

blood pressure can be defined as a ‘‘nondipping blood pressure profile’’ and such individuals are marked as nondippers.

Increased cardiovascular risk and worst prognosis is seen in nondipping hypertensive individuals when compared with individuals of a normal circadian rhythm. Nondippers have autonomic dysfunction, sympathetic system overactivity and high inflammatory activation. Increased serum uric acid is an independent and strong predictor of nondipping pattern. Moreover, release of inflammatory mediators is more common in nondippers and hs-CRP level is also significantly correlated with hyperuricaemia52_.

Sequelae of Hypertension:

WHO classification of stages of hypertension:

Stage 1 no objective signs of organic changes

Stage 2at least has one of the following

Left ventricular hypertrophy

Generalized and focal narrowing of the retinal arteries

Proteinuria and increased serum creatinine (1.2 -2 mg/dl)

Ultrasound or radiological evidence of atherosclerotic plaque

Stage 3both symptoms and signs of organ damage

26 Brain-TIA, stroke, hypertensive encephalopathy

Optic fundi- retinal hemorrhage, exudate with or without papilledema

Kidney-serum creatinine >2mg/dl, renal failure

Vessels-dissecting aneurysm, symptomatic arterial occlusive disease53

The heart:

In hypertensive individuals, cardiac hypertrophy is purely an adaptive mechanism to pressure overload which can lead to dysfunction of myocardium, dilation of heart, CCF and sudden death54_.

Morphology:

Hypertension often induces left ventricular pressure overload and hypertrophy without initial ventricular dilation. As a result, thickening of left ventricular wall causes disproportionate increase in the weight of the heart leading to increase in overall cardiac size. On progression, left ventricular wall thickening imparts a stiffness that impairs diastolic filling, often inducing left atrial enlargement55_.

Clinical presentation:

27

caused by enlargement of left atrium or congestive heart failure may be the first symptom56_.

Blood vessels:

Hypertension accelerates atherogenesis causing degenerative changes in the large and medium sized arterial walls leading to aortic dissection and hemorrhage in the brain.

Morphology:

Two forms of blood vessel disease are associated with hypertension:  Hyaline arteriolosclerosis

 Hyperplastic arteriolosclerosis57.

Although elderly persons even with normal pressure are frequently associated with hyaline arteriosclerosis, this change is more severe in hypertensive individuals58_.

Kidney:

Benign nephrosclerosis:

Defined as renal artery sclerosis with parenchymal defects which includes glomerulosclerosis and prolonged tubulointersititial injury, resulting in reduced functional renal mass59.

Morphology:

28

Histologic examination shows narrowing of the arteriolar lumen due to hyalinization and thickening of the vessel walls (hyaline arteriolosclerosis)54 Clinical Features:

Uncomplicated benign nephrosclerosis rarely causes renal insufficiency and uremia. But usually renal blood flow is moderately reduced and the GFR remains normal or slightly reduced. And rarely, there is mild proteinuria.

Brain:

Lacunar infarctions, slit hemorrhages, hypertensive fatal encephalopathy and massive intracerebral bleed are the consequences of hypertension in the brain and the incidence of these can be reduced by repeated screening for high BP and aggressive drug therapy for the same 54_.

Hypertensive Encephalopathy

Is an emergency and life threatening condition with symptoms of headache, confusion, vomiting, convulsions, coma and death commonly seen in individuals with malignant hypertension.

Eye:

29 Hypertensive retinopathy60_:

Grade 1: increased tortuousity of retinal vessels and silver wiring of retinal artery

Grade 2: in addition to grade 1, there will be nipping of venules at arteriovenous crossing

Grade 3: Grade 2 and flame shape hemorrhage and cotton wool exudates

Grade 4: papilledema, hard exudate and macular star

In malignant hypertension, retinal detachment occurs.

Diagnosis of hypertension:

The hypertensive individuals should have the following assessments:

 A detailed history about the patients and their physical examination

 Screening for important cardiovascular risk factors

 Screening for causes of secondary hypertension

 Identifying cardiovascular complications of hypertension and finding out

other comorbid conditions

 Assessing lifestyles which may be a risk factor for raised BP

 Determining the tolerability and susceptibility for intervention13.

30

nocturia. Characteristically, this headache occurs in the occipital region and most commonly in the morning. Other common nonspecific symptoms related to hypertension are dizziness, palpitations, easy fatigability and impotence.

Breathlessness in hypertensive patients suggests congestive cardiac failure or left ventricular hypertrophy. Pheochromocytoma, a common cause of secondary hypertension presents with sweating, palpitations and headache. Symptomatic peripheral vascular disease and angina indicate the presence of renal artery stenosis caused by atherosclerosis. Hypokalemia related symptoms like muscle cramps and muscle weakness is seen in individuals with primary aldosteronism.

Cushing’s syndrome individuals suffer from increased body weight, menstrual

problems, and recurrent acne over face, polyuria, edema and muscular weaknes.

Malignant Hypertension may presents with the symptoms of severe headache, visual disturbance, seizures, reversible loss of consciousness and symptoms of cardiac failure.3

Young hypertensive patients with a family history of hypertension will commonly show simple Mendelian resistance.

Diagnosis of secondary hypertension:

 Age of onset <30 years or >60 years of age

 Difficult to control after therapy initiation

 Clinical occurance of hypertensive crisis

31

Measurement of blood pressure:

Routinely all adults must measure blood pressure at least once in every 5

years till 80 years of age. For this purpose seated blood pressure will be measured

after 5 minutes of rest. While standing blood pressure will be measured only in

diabetic patients and in older individuals to exclude the possibility of orthostatic

hypotension. Blood pressure must be measured after emptying the urinary bladder

and should be seated atleast for five to ten minutes with back fully supported and

legs which are not crossed resting on the ground The arm used for measurement of

BP must rest on a table, at the heart-level. A sphygmomanometer with stethoscope

and automated electronic device are the commonly used devices11.A cuff of

at least 40% the arm circumference in width should be attached to a mercury or

aneroid manometer and inflated around the extended arm. The cuff must be

deflated at 2 mm Hg per second and the blood pressure must be measured to the

nearest 2mm Hg.

Auscultation over the brachial artery reveals five phases of korotoff sounds when

the cuff is deflated62.

Korotkoff sounds:

These are sounds produced from under the distal half of blood pressure cuff

between the systole and diastole due to complete collapse of artery followed by

reopening with each beat. As the artery wall opens it causes tapping sound. As the

cuff pressure falls below the diastolic pressure, sound disappears as the vessel wall

32

Phase 1first appearance of sounds denoting the systolic pressure

Phase 2 and 3louder sound

Phase 4sounds with abrupt muffling

Phase 5disappearance of the sounds

Phase 5 provides better measurement of diastolic blood pressure than phase 4, not

only because it corresponds directly with measured diastolic pressure but also

because its identification is less subjective.

At least two consistent readings are required for the estimation of blood pressure .

More readings may be required if there are variations in the blood pressure

measurement. At initial evaluation, blood pressure is measured in both the arms.

The higher reading will be used for measurements thereafter. When assessing

cardiovascular risk, blood pressure average measured at separate visits will be

most accurate than the measurements done at a single day visit3

Monitoring of the ambulatory blood pressure:

JNC 7 has recommended monitoring of ambulatory blood pressure only in

special cases like white coat hypertension ,treatment resistance, autonomic failure,

hypotension with symptoms ,episodic hypertension and also to know

“nondippers” in whom the blood pressure will not decrease by >10% at night

time13.

This can be done by an automated device which is capable of documenting

blood pressure at more frequent intervals throughout the day. The measured

33

values. The normal upper limit of ambulatory blood pressure reading is 140/90

mmHg in daytime, 125/75 mm Hg at sleep, and 135/85 mm Hg during continuous

measurement for 24 hours. The home blood pressure recordings can be done by

patients themselves in the morning by using the home monitoring devices64.

Physical Examination:

 Body habitus like weight and height are measured.

 Blood pressure must be measured in both the arms

 Standing BP measurement to rule out postural hypotension.

 In young individuals, lower extremity BP should be measured even if

femoral pulsations are felt.

 Check for hyper and hypothyroidism by palpating neck

 Fundus examination for vascular disease and papilledema

 Auscultation over carotid and femoral artery for bruits

 Auscultation of the heart for loud S2 because of aortic valve closure and

for S4 gallop as a result of atrial contraction.

 Palpation of enlarged and laterally displaced apical impulse due to

hypertrophy of left ventricle13.

 Carotid bruits, cardiac murmer,S3 or S4 heart sound, neurological

deficit, elevated jugular venous pressure, rales, unequal pulses,

34

radiofemoral delay, tendon xanthoma and central obesity on physical

examination needs investigations for target organ damage or secondary

cause of hypertension.61

Diagnosis of Hypertension:13,18

SYSTEM TEST

Renal Microscopic urinalysis, serum uric acid,albumin excretion, serum

BUN and creatinine,Renal USG and angiography.

Endocrine Serum sodium, potassium, calcium,TSH,urine catechol for

pheochromocytoma,urinary cortisol and dexamethasone

suppression test for cushing syndrome,plasma renin and

aldosterone for primary aldosteronism

Metabolic Plasma blood glucose and lipid profile

Other Hematocrit, ECG for left ventricular hypertrophy and

ischaemia,X-Ray for cardiac size and coarctation of aorta,echo for left

ventricular hypertrophy.

Factors Influencing Risk of Cardiovascular Disease:  Age more than 55 years of age

 Male gender

35

 Post menopausal women

 H/O Diabetes Mellitus

 Increased waist hip ratio

 Increased LDL,total cholesterol,low HDL,high triglyceride

 Family history of premature cardiovascular disease with age of onset of less

than 55 years in male and less than 65 years in female.65

MANAGEMENT OF HYPERTENSION: General considerations and goals of treatment:

Primary goal in the treatment of hypertension is prevention of long term

sequelae. Primary concern is to lower systolic blood pressure which is associated

with mortality. Wide pulse pressure reflects high systolic blood pressure and most

accurate predictor of all. High risk individuals can be approached with

nonpharmacological treatment to achieve a significant fall in blood pressure over a

period of 3-6 months. Even after 3 months if the blood pressure is more than

140/90mmHg initiate drug therapy. Discretion is warranted while prescribing

medication for hypertension that may adversely affect cardiovascular risk in other

36

JNC 7 guidelines65 Target blood pressure

Young adults and middle age <140/90mmHg

Diabetic patients <140/80mmHg

Stroke patients <140/85mmHg

Elderly patients with stroke <150/90mmHg

In the absence of hypertensive crisis, blood pressure should be reduced gradually

to avoid cerebral ischemia.

Patient education is more important in treatment plan to promote patient

compliance. Culture and other individual differences among patients should be

taken into consideration before the start of therapy. Physicians should emphasize

that

a) Lifelong treatment is required

b) Symptoms are unreliable tool for severity of hypertension

c) Prognosis improves with proper and continued treatment61.

Primary prevention :

Aims at reducing the incidence of hypertension.

a)Population based strategies: Information and education:

Education about salt intake, diet control and healthy diet through interpersonal

communications and multimedia channels can create favorable environment and

37

Physical activity:

To counter pandemic of obesity in context of nutritional abundance, physical

activity is the public health priority. WHO recommends 30 minutes exercise per

day done atleast 5 times a week. Regular aerobic exercise should be within the

limits of cardiovascular status.

Diet:

Reduce the intake of saturated and tans fatty acids. Adequate dietary intake of

potassium should be there to lower blood pressure and also to prevent stroke and

arrhythmia. Sodium and potassium should be maintained in the ratio of 1:1. Daily

dietary potassium intake should be 50mmol/day.Potassium is rich in fruits and

vegetables. Adequate dietary maintenance of calcium and magnesium are

required.

Limit alcohol intake not more than one ounce (i.e. 30 ml) of brandy, whisky or

rum per day or 24 ounces of beer. DASH diet should be followed which includes

diet rich in fruits and vegetables with limited intake of fat dairy foods, saturated

38

Lifestyle modifications12 Change in blood pressure Fruits,vegetables,diet with low fat Reduce by 6/3mmHg

Moderately intensive aerobic exercise Reduce by 2-5/1-2mmHg

After each cigarette Increase by 10-15mmHg SBP

First morning cup of coffee Increase by 10-15mmHg SBP

10kg weight loss Reduce by 5-20mmHg SBP

DASH diet Reduce by 8-14mmHg SBP

Alcohol moderation Reduce by 2-4mmHg SBP

b) High risk approach:

Middle range of high blood pressure who are not diagnosed as hypertensive

patients but are at risk of developing cardiovascular complications are screened

through this approach. More appropriate for individuals and their physicians but

have little impact on general population. This approach does not alter the

underlying cause of hypertension and deals with only margin of problem. It

requires continued and extensive screening.

Secondary prevention:

Aims to reduce the prevalence of hypertension by early diagnosis and treatment.

This can be done by regular monitoring of blood pressure for all people more than

30 years of age who come in contact with health faculty. New component of

control of non communicable diseases has been added in the job description of

39

Tertiary prevention:

Aims to reduce the disabilities in individuals who have already developed

complications due to hypertension. Family based rehabilitation is necessary.

Drug treatment for hypertension:

Most of the patients will be in need of more than one drug for control of raised

blood pressure. In general, we should either increase the dose of individual drugs

or must add new drugs from different class at 2- to 3-weekly interval time. This

frequent change may be fast or slow which depends on the decision of the

physician. Most of the patients will reach the effective treatment regimen, within 6

to 8 weeks.

Choice of antihypertensives:

It is mostly influenced by the age, ethnicity, and other clinical conditions of the

patient (eg, diabetes mellitus, CAD and Pregnancy) Long-acting drugs with single

dosage per day are always preferred over shortly acting drugs which require

40

Figure 8:ACD Rule:69

Brief comments on drug classes:

Angiotensin-converting enzyme Inhibitors

?Action - blockade of RAAS

?Beneficial effect by preventing breakdown of bradykinin.

? Adverse effects noted are cough ,dose dependent hyperkalemia and rarely

42

Class13 Examples Dosage/Day Other Uses Contraindications

ACE inhibitors

Captopril 25–200 mg PostMI,

Nephropathy

and CHF

Pregnancy, Hyperkalemia,

Renal failure and Bilateral

renal artery stenosis, Ramipril 2.5–20 mg

Lisinopril 10-40mg

Angiotensin Receptor Blockers:

 Action - blockade of AT1 receptor

 Vasodilator

 No cough like ACEI

 No dose dependent adverse effects

 Preferred over ACEI

Class13 Examples Dosing /

day

Other uses Contraindications

Angiotensin II antagonists Losartan 25–100 mg CHF, ACEI cough, Diabetic nephropathy Renal failure, Pregnancy, Hyperkalemia and Bilateral renal artery stenosis Valsartan 80–320 mg

43

Thiazide and Thiazide-like Diuretics:

 Action by excretion of sodium by kidney

 Vasodilator.

 Cause reduction in the incidence of strokes and CAD

 Chlorthalidone is potent and long acting antihypertensive among the

thiazides

Adverse effects

 Hypokalemia can be prevented by combined use of potassium sparing

diuretics

 Hyperuricaemia can be reduced by starting with low dose

 Hyperglycemia can be prevented by avoiding -blockers or by combining

ACEI13

Calcium Channel Blockers:

 Acts by blockade of L type calcium channel in the arterial smooth

muscles

 Two types:

Dihydropyridines which dilates mainly arteries and

non-dihydropyridines which has negative inotropic and chronotropic

property along with vasodilatory property thereby preferred in atrial

fibrillation.

44

 Important adverse effect is peripheral edema, occurring only at high

doses.

Calcium antagonists13

Examples Dosage/Day Other Uses Contraindications

Dihydropyridines Nifedipine 30–60 mg Angina

Heart failure, 2nd

or 3rddegree heart

block

Non-dihydropyridines

Verapamil 120–360

mg

Supra

ventricular

tachycardias,

Angina,

Post-MI. Diltiazem 180-420 mg

Beta Blockers:

 Act by reducing cardiac output and by blocking renin

 Least effective when used in black population

 Not effective in preventing stroke and CAD

 Adverse effects are hyperglycemia, heart block, erectile dysfunction and

fatigability

 Combined alpha and beta blocker dugs like labetalol are used in

45

Beta blockers13

Examples Dosing /day

Other Uses Contraindications

Cardioselective Atenolol 25–100

mg Angina, Sinus tachycardia, Congestive heart failure, PostMI, Ventricular tachyarrhythmias

2nd or 3rd degree

heart block,

sick-sinus syndrome,

asthma, COPD, Metoprolol 25–100

mg

Nonselective Propranolol 40–160

mg Combined Alpha/beta Labetalol 200– 800 mg CHF Carvedilol 12.5– 50 mg CHF Alpha Blockers:

 Act by blocking arterial alpha adrenergic receptors and thus preventing the

vasoconstriction.

 Least used as first line agent

 Mainly used in resistant cases of hypertension

 Usually combined with diuretics to neutralize the metabolic adverse effects

of diuretics

 Beneficial in benign prostate hypertrophy

Alpha antagonists13

Examples Dosing

/day

Other indications

Selective blocker Prazosin 2–20 mg Prostatic hypertrophy

Doxazosin 1–16 mg

Terazosin 1–10 mg

Nonselective blocker

Phenoxybenzamine 20–120 mg

46

Centrally Acting Agents:

 Act centrally by blocking sympathetic outflow

 Alpha methyl dopa is safe for use during pregnancy

 Clonidine patches are available to reduce the withdrawal syndrome of oral

clonidine13.

Direct Vasodilators:  Rarely used

 Diuretics are often required to counteract their fluid retention

 Hypertrichiosis is the main adverse effect of minoxidil

Mineralocorticoid Receptor Antagonists:

 Spironolactone was used in older days for heart failure and increased

aldosterone states in resistant hypertension

 Eplerenone used in treatment of resistant hypertension

 Adverse effects are gynecomastia, erectile dysfunction and hyperkalemia

 Cautiously used in patients with low GFR<50%

Followup visits and Monitoring:

After initiating antihypertensive, patients must come for scheduled followup visits

for dosage adjustment atleast at monthly intervals till the control of BP is

achieved. In patients with stage 2 hypertension and/or with comorbid conditions

and complications more frequent followup visits are needed. Serum levels of

47

times/year. Followup visits can be extended to once in 3- to 6-months after

control of raised BP or with achieved BP goal.68

Hypertensive urgencies and emergencies:

Individuals with markedly elevated BP and with acute end organ damage mostly

need a hospital admission and parenteral drug therapy.

Patients with markedly elevated BP but with no acute end organ damage

doesn’t require hospital admission but needs combination of oral antihypertensive

drugs immediately. They must be evaluated for hypertension associated heart and

renal damage. Any identifiable causes of hypertension should be looked for.70

Special considerations:11

Recommendations First line therapy Second line therapy

Third line therapy

Diabetes RAAS inhibitors

(ACE inhibitor or

angiotensin receptor blockers) Calcium channel blockers or thiazide Calcium channel blockers ,RAAS inhibitors and Thiazides

CKD RAAS inhibitors Calcium

channel blockers or thiazide Calcium channel blockers ,RAAS inhibitors and Thiazides

CAD Beta blocker and

48

Stroke RAAS inhibitors Calcium

channel

blockers or

Thiazides

Calcium channel

blockers , RAAS

inhibitor and

thiazide

Cardiac Failure RAAS inhibitors,beta

blocker,Diuretics and

Aldosterone

antagonist

Amlodipine

MANAGEMENT OF HYPERURICAEMIA IN HYPERTENSIVE

PATIENTS:

Non pharmacological management:  Low purine diet

 Weight reduction

 Avoidance of alcohol

 Avoidance of drugs causing hyperuricaemia like thiazides, cytotoxic drugs

etc.

Pharmacological treatment:

Benzbromarone, allopurinol, probenecid, fenofibrate and febuxostat are the

known drugs for the treatment of hyperuricaemia. But these agents can lead to

renal stones by an unexpectedly stronger uricosuric effect and there is a possibility

of attenuating uric acid lowering effect by increasing oxypurinol elimination in

49

These agents have specific side effects like allopurinol causing dose related

gastrointestinal adverse effects and severe rashes ,benzbromarone causing

hepatotoxicity and they commonly cause idiosyncratic adverse effects, which

discourage the use of these agents in hypertensive patients with hyperuricaemia.

Moreover they donot improve endothelial cell function and hemodynamic

impairment and so cannot prevent cardiovascular mortality in hypertensive

patients.23

LOSARTAN:

A promising agent for the treatment of hyperuricaemia in patients with

hypertriglyceridaemia or hypertension.

Uricosuric mechanism :

Losartan potassium being an orally active angiotensin II receptor antagonist is

commonly used in the treatment of hypertension. Its active metabolite E-3174 with

long t1/2 is also a potent antagonist at the AT1 receptor. The first observation of

uricosuric effect of losartan which acts by increasing urinary uric acid excretion

thereby reducing serum uric acid level was noted in a pilot study done in healthy

volunteers in the year 1992.

The fractional clearance of uric acid is expected during the first few hours of

drug intake. Though angiotensin reduces uric acid renal excretion, blockade of the

same is not responsible for the uricosuric effect of losartan. This was further

proved by unaltered uric acid levels after reducing sodium intake or treatment with

50

exchanger URAT1” in the kidney .Blockade of this transporter will inhibit the

urate reabsorption in the proximal tubule of kidney and so promoting uric acid

excretion.71

In most clinical studies, losartan 50 mg once daily dosage increased the

fractional elimination of uric acid.71 These studies showed that after four weeks

treatment with losartan there was a significant reduction in serum uric acid with

corresponding increased excretion of urinary uric acid72 The increase was

moderate, from 3 to 30% and uricosuric effect was maintained even after drug

discontinuation for 3–4 weeks of treatment. Doubling the losartan dose did not

show any further reduction in SUA levels.

Losartan can be combined with diuretics which usually cause hyperuricaemia

as an adverse effect on their chronic use. Losartan raises the urinary pH

significantly which counterbalances the risk of urolithiasis associated with raised

uric acid elimination. This unique property is not seen with other uricosuric drugs.

Due to this additional uricosuric property, Losartan causes significant reduction in

BP71

Based on literature review hyperuricaemia is an important risk factor for

hypertension related morbidity and mortality like stroke and cardiovascular events,

so Losartan is a good antihypertensive in hypertension associated with

hyperuricaemia. Genetic polymorphisms in the URAT1 transporter are associated

with raised BMI, waist circumference, HDL-c, and the syndrome X in

51

dyslipidemia. Losartan has renoprotective effect in hypertensive patients by

reduction in urate and lowering blood pressure23

Description

Losartan potassium is a non-peptide molecule.Its empirical formula is

C22H22ClKN6O.

Figure 9:Structural formula of losartan76:

It is soluble in water and alcohols but less soluble in organic solvents like

acetonitrile and methyl ethyl ketone.

5-hydroxymethyl group oxidation in the imidazole ring leads to the formation of

active metabolite of losartan.

CLINICAL PHARMACOLOGY Mechanism of Action

Losartan being an Angiotensin II receptor blocker will bind with the AT1 receptor

which is competitive in nature but the inhibition of Angiotensin II is often

52

 Dissociation kinetics of losartan from AT1receptor is very slow

 Losartan induced receptor internalization

 Alternative binding sites for losartan on the AT₁receptor

This insurmountable antagonism leads to sustained receptor blockade of losartan

even in the presence of excess levels of endogenous ligand and with forgotten

doses of losartan.

Losartan potently and selectively inhibits the biological response of Angiotensin II

which includes

 Contraction of vascular smooth muscle

 Rapid pressor responses

 Slow pressor responses

 Release of adrenal catecholamines

 Vasopressin release

 Aldosterone secretion

 Enhancement of noradrenergic neurotransmission

 Increase in sympathetic tone

 Changes in renal function

Potential role of Aldosterone:73

MECHANISM PATHOPHYSIOLOGIC EFFECT

Increased Na+ and water

retention

Edema and elevated cardiac filling pressures

Alterations in the sodium

channel expression

Increase in the excitability and contractility of

cardiac myocytes

Reduced myocardial NE

uptake

Potentiation of NE affects: myocardial

remodeling and Arrhythmogenesis

Myocardial fibrosis Remodeling and ventricular dysfunction

Reduced baroreceptor

sensitivity

Reduced parasympathetic activity ; high risk of

sudden cardiovascular death

K+ and Mg2+ loss Arrhythmogenesis ; high risk of death

54

The metabolite EXP 3174 being 10 to 40 times more potent than the parent drug

losartan, is also a reversible and noncompetitive inhibitor at the AT1 receptor.

Losartan will not block ion channels or hormonal receptors and it does not affect

the autonomic reflexes. It does not block the degradation of bradykinin

Pleiotrophic effects of Losartan:

 Losartan will significantly reduce the proteinuria, fractional elimination

of albumin and IgG. Moreover it will maintain glomerular filtration rate.

 Losartan can cause persistent decrease in serum uric acid levels

 Act as a competitive antagonist of the thromboxane A₂ receptor and

therefore can attenuate platelet aggregation.

 Its active metabolite EXP 3179 will reduce the COX-2 mRNA

upregulation and so decreasing the prostaglandin generation.

 Losartan in the therapeutic dose of 50 mg daily significantly reduces

serum total cholesterol and total triglyceride levels.74Lipid lowering

property of angiotensin receptor blocker is due to different mechanisms

 Activation of PPAR gamma which regulates lipid metabolism

 Interaction between the lipid metabolism and angiotensin system75

Pharmacokinetic properties Absorption:

Losartan is absorbed well on oral administration and the first-pass metabolism in

55

inactive metabolites. The systemic bioavailability of losartan is nearly 33% and

the peak plasma concentrations of losartan and EXP 3174 are achieved in 1 hour

and in 4 hours respectively and the plasma half-lives being 2.5 and 6-9 hours,

respectively. No interactions with the food.

Distribution:

It is 99% plasma protein bound drug with volume of distribution around thirty

four litres .It does not cross the BBB

Metabolism :

The biotransformation of losartan is through CYP2C9 and CYP3A4 in the liver

and fourteen percent is converted into EXP 3174.

Excretion:

The clearances of losartan and EXP 3174 are due to renal and hepatic elimination

which is affected in individuals with impaired hepatic function. The kinetics of

losartan and EXP 3174 have linear relationship until the dose of 200mg. Losartan

and EXP 3174 cannot be removed by using haemodialysis.76

THERAPEUTIC USES Hypertension :

Losartan is used in the treatment of hypertension. In clinical studies, once-daily

administration of 50mg losartan for stage 1 and 2 essential hypertension showed

significant reduction in both systolic and diastolic BP and the antihypertensive

56

paralleled the natural diurnal rhythms. Discontinuation of losartan will not cause

rebound hypertension.

Hypertensive patients with left ventricular hypertrophy:

A reduced incidence of stroke was noted in these patients during losartan

treatment

Reno protective in patients with DM and nephropathy:

Losartan delays the progression of renal disease by reducing the incidence of

raised serum creatinine, end stage kidney disease and death. It causes a reduction

in proteinuria.

Heart failure:

Indicated in improving symptoms and reducing mortality

Treatment of hyperuricaemic patients with hypertension:

Losartan is indicated in hypertensive patients with hyperuricaemia for reducing

serum uric acid and for increasing the urinary uric acid elimination.

Gout:

Losartan has a modest uricosuric effect and may be an option for those who are

intolerant to probenecid and are hypertensive.

Portal hypertension:

Losartan is safe and potent agent in the treatment of portal hypertension with

57

Dosage of losartan:

Losartan effects are not affected by food intake.

Hypertension and hypertensive patients with hyperuricaemia

50 mg administered once daily and the maximal effect is seen after 3-6 weeks of

drug therapy.

For reducing the incidence of stroke in hypertensive patients with CAD

The initial dose is 50 mg of losartan given once daily. A low dose of diuretics like

thiazide can be combined or else the dose of losartan can be raised to 100 mg/day

based on the BP.

Reno protective dose in diabetic patients with macroalbuminuria

Initial dose is 50 mg /day. The dose can be up titrated to 100 mg/day based on the

BP. It can be combined safely with insulin, oral hypoglycemic agents and other

antihypertensive drugs.

In volume depleted patients

Initial dose of 25 mg/day is recommended

Patients with renal dysfunction

Generally no dosage alterations are needed in mild impairment. But in moderate to

severe renal failure and in patients on dialysis, the initial dose may be reduced to

58

Patients with hepatic dysfunction

Dosage reduction is compulsory and the initial starting dose preferred must be low

as 25mg

Pediatrics

Losartan use in individuals who are less than 18 years is generally not

recommended.

Old age

Up to 75 years of age: No dosage alteration is required More than 75 years of age: A low initial dose of 25 mg/day.

Contraindications •Pregnancy

Losartan is contraindicated during pregnancy and requires immediate drug

stoppage if pregnancy is detected. Animal studies with losartan have demonstrated

fetal and neonatal injury and death. In humans beings the risk is more during the

second and third trimester because the fetal renal perfusion depends on RAAS

development which begins during the second trimester.76

•Hypersensitivity

Any history of hypersensitivity to losartan, other ARBs or any excipients added

59

Drug interactions:

In clinical pharmacokinetic studies, no significant drug interactions of losartan

were noted with hydrochlorothiazide, cimetidine, ketoconazole, erythromycin,

digoxin, warfarin and phenobarbital. Fluconazole and rifampicin will reduce the

levels of active metabolite of losartan.

Concomitant use of potassium-sparing diuretics or foods rich in potassium can

result in fatal hyperkalemia. On the other hand antihypertensive effect of losartan

may be reduced by NSAIDs such as indomethacin and steroids.76

Undesirable effects :

Losartan is generally well-tolerated and the overall occurrence of adverse effects

of losartan is similar to placebo. Adverse effects are usually mild and transient in

nature and do not require stoppage of drug. The most common adverse effects

observed with Losartan therapy are dizziness,easy fatigability, vertigo,

hyperkalemia, hypotension and gastrointestinal adverse effects like

nausea,vomiting and diarrhea while the rare and uncommon side effects are

60

STUDIES RELATED TO PLEIOTROPIC EFFECTS OF LOSARTAN:

1. A study on losartan 50 mg when given for 1 month in 10 hypertensive patients

showed decrease in proximal sodium reabsorption,microalbuminuria and increase

in renal uric acid clearance without altering GFR and renal plasma flow.Renal

function was well preserved which may be of clinical interest when adjuant

diuretic therapy is required.77

2. Lang RM et al conducted a study in heart patients which showed that 12 weeks

oral administration of losartan was well tolerated .Functional capacity and clinical

status of patients with heart failure in whom treatment with ACE inhibitor when

replaced with losartan for 12 weeks remained the same. Treadmill exercise time ,6

minutes walk test,dyspnea fatigue index and left ventricular ejection fraction also

did not change significantly when an ACE inhibitor was replaced by Losartan.So

Losartan was well tolerated in patients with heart failure and was comparable to

enalapril with regard to improving exercise tolerance78.

3. A study done by Schneider AW et al, reported that Losartan was safe and highly

effective in the treatment of portal hypertension in patients with cirrhosis and

portal hypertension without compromising renal function and none of the patients

had deterioration of liver function79.

4. A study on 13 hypertensive patients with hyperuricaemia and gout who were on

losartan 50 mg once daily or irbesartan 150 mg for 4 weeks showed a decrease in

61

increasing losartan dose to 50 mg BD did not further decrease serum uric acid.This

demonstrated dose dependent uricosuric effect of losartan80.

5. Kramer C et al demonstrated detectable serum levels of EXP3179 in patients in

concentrations that exhibit anti-inflammatory and antiaggregatory property in vitro

by abolishing COX2 mRNA upregulation and COX dependent thromboxane A2

and prostaglandin F2alpha generation. This proved the anti-inflammatory and

antiaggregatory properties of losartan81.

6. The Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension

Study demonstrated the superiority of losartan compared with adrenergic receptor

antagonist (atenolol) with regard to reducing stroke incidence in hypertensive

patients with associated left ventricular hypertrophy. The losartan group showed

less frequent new onset diabetes mellitus with better tolerability than the atenolol

group82.

7.A study done in 25 hypertensive patients after 3 months treatment with either

losartan or trandopril showed improvemet in insulin sensitivity by decreasing

sympathetic system activation and reduction in HbA1c due to low in vitro

formation of advanced glycated end products in losartan group.Von willebrand

factor and homocysteine levels were also reduced in losartan group when

62

8. A study done by Rayner BL et al, on 59 patients with hypertension and

hyperuricaemia associated with diuretics were added on either Losartan or

candesartan.Both the drugs lowered blood pressure and fibrin which may explain

reduction of stroke in hypertensive patients but losartan had an additional

advantage of reducing uric acid84.

9.A study done by Seok Min Kang et al explained the anti-inflammatory and

antiproliferative properties of losartan in which it inhibited the uric acid

stimulated proliferation and inflammatory signaling by modulation of uric acid

transporter in cultured rat aortic vascular smooth muscle cells(33% reduction

p<0.05).This may predict beneficial effect of losartan on vascular changes85.

10. Nindita Y et al demonstrated the effect of losartan and benzbromarone on the

level of urat1 mRNA in transfected HEK 293 cells. Losartan caused significant